Showing papers in "Journal of Clinical Investigation in 1962"

A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: a correlated clinical, biochemical, and morphological study

Abstract: energy liberated in respiration is conserved in the form of ATP 1 (2). Normally the respiration of isolated mitochondria is obligatorily coupled to the formation of ATP from ADP and inorganic phosphate, and thus cannot proceed at any appreciable rate if either of the latter components is absent from the incubating medium (3). This phenomenon, usually termed respiratory control, is generally considered to be a reflection of the capacity of the living cell to regulate its respiration according to its actual demand of energy. It was found that in the present patient this ability of the isolated skeletal muscle mitochondria was severely

Forearm metabolism in obesity and its response to intra-arterial insulin. characterization of insulin resistance and evidence for adaptive hyperinsulinism*

Abstract: Obesity is considered ordinarily to be a consequence of overeating by an otherwise normal person, but the notion persists that there may be some underlying metabolic defect. The man of 70 kg, on becoming 20 per cent overweight, doubles his adipose organ mass (3). If obesity is viewed as a state of chronic substrate excess necessitating increase in fat storage of this magnitude, one might indeed predict that certain metabolic adjustments would occur, resulting in alterations in, but not implying a primary disturbance of, intermediary metabolism. Metabolism of obese subjects has been examined by measuring metabolic events in the forearm, which is predominantly skeletal muscle and adipose tissue, in the search for answers to the following questions. 1) What departures from normal take place in basal forearm metabolism of obese subjects and what light do these differences shed on adaptation to chronic substrate excess? 2) Is \"simple\" obesity related to maturity onset diabetes mellitus, in which obesity is common? Because resistance to exogenous insulin occurs in untreated maturity onset diabetes (4), response to intra-arterial -insulin was examined in simple obesity. From the observations it became clear that there are a number of similarities in metabo-

Interrelations of vitamin b12 and folic acid metabolism: folic acid clearance studies

Abstract: The studies of many investigators have led to a unified concept of the megaloblastic anemias as a single morphologic entity due to defective nucleoprotein synthesis from various causes. The vast majority of patients with megaloblastic anemia have been found to have deficiency of vitamin B12, of folic acid, or of both vitamins. For this reason, the possible interrelations of these two vitamins have long piqued the curiosity of investigators (1, 2). Orally administered or injected pteroylglutamic acid (PGA) (folic acid) has been reported to disappear rapidly into the tissues of vitamin B12(leficient patients, as manifested by rapid disappearance of Streptococcus faecalis activity from serum and urine (3-6). 'The purpose of the present investigation was to determine whether the rapid disappearance of folic acid activity for S. faecalis from the serum of subjects with pernicious anemia reflects tissue depletion of folic acid, as believed by prior investigators, or instead indicates inadequate utilization of folic acid due to vitamin B12 deficiency. Prior results of part of these studies (7-10) suggest that the latter is the case. Incidental to these observations, the effect of intravenously administered PGA on serum vitamin B12 and on erythrocyte folic acid activity was determined. The studies here presented elaborate on our preliminary reports (7-10), indicating that folic acid activity \"piles up\" in human serum in the presence of vitamin B12 deficiency. The accumulation of this folic acid activity (probably N5methyl-tetrahydrofolic acid) provides direct evidence of deranged folic acid metabolism due to vitamin B12 deficiency. This folic acid-vitamin B12 interrelationship may explain much of the confu-

Regional pulmonary function studied with xenon133

Abstract: A radioactive isotope of the inert gas, xenon, was used in conjunction with externally placed scintillation counters to estimate separately the function of six different regions of the lung. By comparison of external counting rates after a single breath and after rebreathing an air-xenon mixture, it has been possible to compute an index of relative ventilation that is independent of the volume of lung within the counting field. Determinations were made at two levels of inspiration in order to compare the distribution during normal quiet breathing with the distribution after a single full inspiration. By the intravenous injection of dissolved xenonia during breath holding, the relative perfusion of lung in different regions has been determined. ln 21 seated normal subjects, it was found that the lower portion of the lung is somewhat better ventilated than the upper portion, but receives a much greater fraction of the total pulmonary blood flow; the distribution of inspired air is slightly more uniform on deep inspiration than during quiet breathing; the middle and lower portions of the lung are better ventilated on the left than on the right during deep inspiration; and the lower portion of the lung is probably better perfused on themore » right than on the left. Forty patients with various cardiac or pulmonary disorders were studied, and four illustrative cases are presented. Two of these illustrate the differences in regional distribution of disordered function that may occur in patients with pulmonary emphysema. The third patient demonstrates the value of the technique in assessing lobar function after transposition surgery, and the fourth patient illustrates normally distributed ventilatory function despite a disturbed distribution of perfusion in uncomplicated mitral stenosis. The advantages and disadvantages of this method in comparison with the oxygen15 technique of West and co-workers are discussed. It appears that the xenon technique described is capable of extensive application to both investigative and clinical problems.« less

Interrelation of uric acid and ethanol metabolism in man

Abstract: Traditionally, the drinking of large amounts of alcoholic beverages has been considered a common predisposing or precipitating cause of gout (1). Thus far, however, the possibility of a relationship between ethanol and urate metabolism does not seem to have been investigated. In an attempt to evaluate a possible effect of ethanol on uric acid metabolism, we have studied serum uric acid levels in patients intoxicated with ethanol. Having observed that ethanol leads to an elevation of serum uric acid concentration, we investigated the mechanisms of this effect. None had gout or any known cause of secondary hyperuricemia. Renal function was normal as judged by blood urea concentration and urinary sediment, there was no major hematological abnormality, and all except Subject 8 were afebrile. Although all except Subject 14 admitted considerable ethanol intake in the past, at the time of the study none showed clinical or laboratory evidence of liver disease except Subjects 1, 4, and 8, who had compensated hepatic cirrhosis. Subject 14 suffered from chronic idiopathic adrenal insufficiency and was being treated with desoxycorticosterone acetate (DOCA) at the time of the study. Studies in intoxicated patients. Sixteen patients were studied when admitted to the hospital acutely intoxicated with various alcoholic beverages. Venous blood was drawn for chemical determinations at the time of admission and at intervals thereafter. In each patient, the final serum uric acid concentration was compared with the initial value. The mean of the individual differences was calculated and its degree of significance tested by the t test (2). Metabolic Ward before, during, and after ethanol administration. The amount of ethanol administered is indicated individually with the results observed in each of these patients. A. Intravenous infusions. In three subjects, 13, 14, and 15, ethanol was given after an overnight fast as a continuous infusion of a 15 per cent by volume solution in isotonic saline. In Subject 15, this was preceded by a 2½-hour control period during which saline solution was administered. In Subject 13, a control test with isotonic saline solution alone was done on another day. B. Oral tests. After an overnight fast, Subjects 4, 16, 17, and 22 were studied for a 2½-hour control period during which water flavored with grapefruit juice was administered orally to compensate for urinary water losses. Thereafter, in addition to the water, the patients were given ethanol in concentrations varying from 10 to 35 per cent by volume. …

Influence of flow properties of blood upon viscosity-hematocrit relationships.

Abstract: The influence of the red cell concentration (per cent hematocrit) upon blood viscosity is well known. Some physiology texts (1) portray this relationship by means of a diagram in which relative or apparent viscosity is plotted against the per cent hematocrit (Figure 1). It has been demonstrated that besides the effect of cell concentration the viscosity of blood varies both as a function of the shearing stresses developed within the fluid and the rate at which these forces are distributed between the adjacent fluid elements during flow (2-4). The relationship or ratio of shear stress to the gradient of velocity, or shear rate, defines the viscosity of the fluid in the absolute dimensions of dyne-seconds-cm', or poise. In his original definition of this property of fluids, Newton made the assumption that the ratio of shear stress to shear rate was constant for all fluids. Contemporary studies of the flow properties of various complex fluids have shown that many of these demonstrate a disproportionate change in shear stress as shear rate increases or decreases; in fact, rheological nomenclature is based upon the direction in which this ratio changes with change in shear rate (5, 6). The viscosity of blood has been shown to exhibit this type of shear rate dependence, i.e., viscosity decreasing as shear rate rises (4). At the time Poiseuille made his classic contribution to the dynamics of flow in tubes, it was not known that complex fluids such as blood rarely maintained a constant of proportionality between shear stress and shear rate. The Poiseuillian equation therefore has as its first condition that the fluid under study be a Newtonian fluid, i.e., one with a constant ratio of shear stress to shear rate. Many workers have pointed out that blood is a non-Newtonian fluid (3, 7, 8), that the law of Poiseuille cannot be directly applied to the conditions of flow in the capillary circulation (9, 10), and that the viscosity of blood is anomalous (11-13). In all of these references , however, capillary tube viscometers or the vessels of experimental animals were used as the testing devices. The use of a capillary viscometer, which so well imitates the anatomy of a blood vessel, has certain practical limitations that make it difficult to derive values of blood viscosity over the lower ranges of shear rate (below 100 sec') (14, 15). The interpretation of the results of viscometry of such …

Immunoglobulin levels from the newborn period to adulthood and in immunoglobulin deficiency states.

Abstract: Beta-2A globulin and the 7S and 19S gamma globulins are the major proteins of the serum derived from the immune system. Collectively they have been termed the immunoglobulins. The 19S gamma globulin, also known as the gamma-1 macroglobulin, the 82 macroglobulin or 82M, has been the subject of intensive study in recent years. The rheumatoid factor as well as a variety of antibodies fall into this protein group, and abnormally high levels are found in Waldenstroem's macroglobulinemia. Less is known about 82A globulin (gamma 1-A). It is like gammaglobulin in that it has a sedimentation constant of 7S, but contains more carbohydrate (1). Recent observations imply that it is the carrier of the reaginic activity of the serum (2). All of immunoglobulins are easily detectable in normal adult serum by immunoelectrophoretic analysis. 82A and 82M are absent in cord serum, and in agammaglobulinemia all three immunoglobulins are absent or in greatly reduced concentrations. Other antibody deficiency states have been described in which only one or two immunoglobulins are in low concentration (3-6). The present paper reports the levels of the immunoglobulins in cord serum and in the serum of infants, children, and adults as determined by a method based on a combination of immunoelectrophoretic analysis and the quantitative precipitin reaction (7). The data reveal a variable rate of maturation of the synthetic mechanisms for these proteins that is not apparent from semi-quantitative estimates based on simple immunoelectrophoretic analysis of serum. Also reported are the

Red cell, plasma, and blood volume in healthy women measured by radiochromium cell-labeling and hematocrit

Abstract: In a previous study of 201 healthy men (1), red cell volume (Vrbc) was measured by a modification of Sterling and Gray's radiochromium method (2), and whole blood and plasma volumes (Vwb and Vpl) were derived from venous hemiatocrits. The influence of factors other than body size on the variance of the data was studied, and standards for predicting normal volumes were derived. The present report describes a similar examination of 101 women.

Specificity of the human intestinal disaccharidases and implications for hereditary disaccharide intolerance.

Abstract: The existence of several different a-glucosidases has recently been demonstrated in extracts of pig intestinal mucosa (1-7). These enzymes have varying specificity for disaccharides with aD -glu-copyranoside structure (e.g., maltose, sucrose, iso-maltose, trehalose), and thus the intestinal hy-drolysis of these sugars is caused by a more complicated enzyme mixture than had been previously believed (8, 9). The 8-glucosidase and /3-galactosidase activities of extracts of pig intestinal mucosa, in contrast, seem to be exerted by one enzyme, intestinal lac-tase (10, 11). It is not known whether the specificity of the human intestinal disaccharidases parallels that of the pig enzymes. This question is of clinical importance , however, since several cases of hereditary inability to digest certain disaccharides have been recently described, and are apparently caused by inherited deficiency of single intestinal disacchari-dases (12-19). Since the human intestinal content, obtained by a catheter during the digestion of a meal, contains essentially no disaccharidases (20, 21), this material cannot be used for the study of the specificity of these enzymes. Therefore homogenates have been prepared of human intestinal mucosa, obtained from pieces of small intestine cut out during surgical operations. These homogenates had powerful disaccharidase activities, and the speci-ficity of the enzymes responsible for these activities has been studied by heat inactivation. MATERIALS AND METHODS Homogenates of human intestinal mucosa. Two samples were obtained, one from the distal part of the jejunum, and the other from the distal part of the ileum. 1) Jejunal sample, from a 40 year old woman; resection of the middle part of the small intestine was indicated by an intestinal tumor. From an 8-cm piece of normal intestine, located in the distal decimeters of the jejunum, 1.6 g of mucosa was scraped off with a glass slide. The mucosa was homogenized for 1 minute in an Ultra-Tur-rax homogenizer with 4.8 ml of 0.9 per cent NaCl, the tube being chilled with crushed ice during homogenization. After removal of nuclei and greater cell debris by cen-trifugation in an ordinary laboratory centrifuge (Wifug, rotor no. 103-30A, 4,000 rpm) for 10 minutes, the opales-cent supernate, which contains the disaccharidases (22), was used for analysis. 2) Ileal sample, from a 26 year old woman suffering from chronic ulcerative colitis; re-operation of ileocecal anastomosis indicated by abdominal abscess. A 15-cm piece of the distal part of the ileum was removed. The intestinal wall of this piece showed considerable induration, but the mucosa appeared …

Some effects of human growth hormone on renal hemodynamics and on tubular phosphate transport in man.

Abstract: It has been repeatedly shown that human growth hormone (HGH) affects phosphorus metabolism in patients with hypopituitarism and in normal subjects. Injection of HGH leads to a decrease of urinary phosphorus within a day (1-3). Whereas serum phosphorus does not change or rises only slightly in short-term experiments (1), it has been reported that it rises with long-term treatment (4). Whereas the decrease of urinary phosphorus associated with an unchanged or rising serum phosphorus suggests that growth hormone decreases renal clearance of phosphate, the mechanism for these effects has not been defined. In the dog, growth hormone has been shown to raise glomerular filtration rate (GFR), renal plasma flow (RPF), tubular maximal secretion of para-aminohippurate (TmPAH) (5-7), and tubular maximal reabsorption of sulfate (Tmso4) (8). Effects on renal phosphate clearance have not been reported. The present study was undertaken to determine whether HGH affects the ability of the human kidney to reabsorb phosphate. For this purpose, maximum tubular phosphate reabsorption (Tmpo4) was measured before and after administration of growth hormone. Effects of the hormone on GFR and on RPF were also studied. The results indicate that HGH increases the phosphate Tm, the GFR, and the RPF.

The role of the renin-angiotensin system in the control of aldosterone secretion*

Abstract: Within the last year, evidence (1-4) has accumulated to show that the kidney secretes a hormone which is a prime regulator of aldosterone secretion. The renal origin of an aldosteronestimulating hormone (ASH) has been demonstrated following acute blood loss (1-3), during chronic thoracic caval constriction (4), and during chronic Na depletion (4). Nephrectomizedhypophysectomized dogs failed to respond to acute hemorrhage with an increase in aldosterone secretion, and acute bilateral nephrectomy of hypophysectomized caval and hypophysectomized Nadepleted dogs resulted in a marked drop in aldosterone secretion. Furthermore, crude saline extracts of kidney produced a striking increase in aldosterone secretion (1-5). In malignant experimental renal hypertension, hyperaldosteronism was consistently present (6). These findings and the reports that renin preparations (6) and synthetic angiotensin II (6-8) increase the rate of aldosterone production suggest the possibility that ASH is renin. The present experiments were undertaken to determine the chemical nature of this ASH by fractionation of crude kidney extracts for aldosterone-stimulating and pressor activity. The renin content of kidneys from dogs with thoracic caval constriction and secondary hyperaldosteronism and from normal dogs has been compared. Since dogs with thoracic caval constriction and Na-depleted dogs do not have hypertension, the response in blood pressure to synthetic angiotensin

Effects of sulfhydryl inhibition on red blood cells. ii. studies in vivo

Abstract: Evidence is presented that the activity of the hexose monophosphate (HMP) pathway of red cells, assayed by r4C02 production from glucose-lJ4C, is regulated primarily by glutathione. Methemoglobin had little, if any, effect on the activity of this pathway. Increasing the ratio of oxidized to reduced glutathione, either by peroxidizing GSH to GSSG or by partially blocking GSH with NEM, increased the rate of HMP pathway metabolism. Complete blockage of cellular glutathione by NEM depressed the bulk of HMP pathway activity, despite little or no effect on the Embden-Meyerhof pathway. Sustained low levels of hydrogen peroxide, whether generated by aerobic oxidases or by the coupled oxidation of ascorbic acid with oxyhemoglobin, stimulated the HMP pathway of cells. This stimulation was potentiated by blocking catalase and was prevented by blocking GSH. The oxidation of NADPH by Hz02 in hemolysates was specifically dependent upon the presence of GSH. These results substantiate the existence in human red cells of the glutathione peroxidase mechanism proposed by Mills, whereby GSH protects cellular constituents such as hemoglobin from oxidative damage induced by HzOz. Oxidative denaturation of oxyhemoglobin to metand sulfhemoglobin by HpOz-generating mechanisms is markedly potentiated in cells lacking sufficient GSH, and commences only after GSH levels approach zero. In contrast, oxidationreduction catalysts such as methylene blue and acetylphenylhydrazine catalyze the direct oxidation of NADPH and hemoglobin, as well as GSH, by molecular oxygen. Although GSH is partially protective against these agents, they appear to damage red cells by virtue of their ability to bypass the GSH peroxidase mechanism and to cause oxidative injury despite persisting GSH.

Metabolic adaptations to a "stuff and starve" feeding program. I. Studies of adipose tissue and liver glycogen in rats limited to a short daily feeding period.

Abstract: Many obese people consume most of their food within a relatively short period each day. These people eat little or no breakfast or lunch but eat voraciously during the evening (1, 2). Stunkard, Grace and Wolff (3) have used the term, \"nighteating syndrome\" to describe this pattern of eating and suggested that this pattern is the result of psychological factors. Some strains of rats can be trained to eat sufficient food in 1 hour each day to permit normal rates of growth (4) and studies of the respiratory quotients of these animals indicate increased lipogenesis (5). Tepperman and Tepperman (6) have shown that liver slices from rats trained in this way show increased incorporation of acetate1-C'4 and glucose-U-C14 in vitro, as well as a threeto fourfold increase in hexose monophosphate shunt dehydrogenase activity. However, lipogenesis in liver represents only a small fraction of the total lipid synthesis in the intact animal. Adipose tissue contributes the major portion (7). These observations coupled with the unusual eating pattern seen in many obese people prompted this study of adipose tissue and liver in rats allowed access to more food than they were able to consume for 2 hours out of each 24, for periods of 1 to 7 days. Studies were made of acetate-l-C'4 incorporation into lipids by adipose tissue and liver slices in vitro, free fatty acid (FFA) content of adipose tissue, glucose-6phosphate (G-6-P) dehydrogenase and 6-phosphogluconic (6-P-G) dehydrogenase activity of adipose tissue and liver homogenates and liver glycogen.

The mechanism of antidiuresis associated with the administration of hydrochlorothiazide to patients with vasopressin-resistant diabetes insipidus.

Abstract: Laragh, Heinemann, and Demartini first reported that the administration of chlorothiazide during water diuresis results in an increased rate of solute excretion without significant changes in the rate of urine flow (1, 2). This effect was interpreted as indicating that the drug interferes with solute (sodium) reabsorption in the distal portions of the nephron where urinary dilution occurs. Similar evidence supporting the concept that chlorothiazide impairs sodium reabsorption at diluting sites in the distal convolution has been presented elsewhere (3). Such a site of inhibition of sodium reabsorption readily accounts for the increased urinary osmolality observed when thiazide derivatives are administered acutely.' Crawford and Kennedy, however, observed that the chronic administration of thiazide derivatives to animals with pituitary diabetes insipidus, and to patients with pituitary or nephrogenic diabetes insipidus, results in a striking diminution in urinary volume as well as an increased urinary osmolality (5). The latter observations have been

Effects of oxygen breathing on the heart rate, blood pressure, and cardiac index of normal men—resting, with reactive hyperemia, and after atropine*

Abstract: Oxygen breathing has been used extensively to treat a wide variety of clinical disorders. An understanding of its effects on the normal circulation, at rest and under conditions of increased cardiac output, is fundamental to the understanding of the efficacy of oxygen therapy in clinical situations. Furthermore, interpretation of physiologic data concerning the effects of hyperoxia on the regional circulations requires definition of any changes in cardiac output or over-all peripheral circulation that occur during oxygen breathing. This investigation was undertaken for two purposes: 1) to evaluate the effects of oxygen breathing on the heart rate, systemic blood pressure, and cardiac index of normal men, resting, after atropine, and subjected to the circulatory stress of reactive hyperemia; and 2) to study the higher ranges of oxygen-sensitive chemoreceptor activity in man.